Field of Invention
The present invention relates to sustained release oral dosage form of a dalfampridine pharmaceutical tablet that can be administered once daily.
Description of Related Art
Dalfampridine, also named as 4-aminopyridine, 4-AP, or fampridine, is an organic compound with the chemical formula C5H4N—NH2. It is used as a research tool, in characterizing subtypes of the potassium channel. It has also been used as a drug, to manage some of the symptoms of multiple sclerosis (MS), and is indicated for symptomatic improvement of walking in adults with several variations of the disease.
The safety and effectivity of dalfampridine are highly concerned. In clinical trials of dalfampridine extended release tablets in patients with MS, the incidence of seizures appeared to be dose related. Furthermore, dalfampridine plasma concentrations measured in patients who have experienced seizure have ranged from 104 to 475 ng/mL, which further suggesting that seizure incidence appears to be dose dependent. Although it is difficult to determine the temporal proximity of the dalfampridine plasma measurements to the initiation of seizure activity, it appears that a plasma dalfampridine concentration of approximately 100 ng/mL may be considered a likely threshold for increased risk of seizure in the absence of other risk factors (Clin Ther., 2012, 34(5), 1056-1069). In addition, it has been reported that if plasma concentrations were lower than 13 ng/mL, low percentage changes in walking speed in MS patients were observed; 13 ng/mL is equivalent to the average trough concentration achieved with 10 mg extended release tablets, twice daily (Current Medical Research & Opinion Vol. 29, No. 12, 2013, 1627-1636).
The approved drug product in the United States, AMPYRA®, is an extended release tablet designed for twice-daily oral administration. Each tablet contains 10 mg active pharmaceutical ingredient which is dalfampridine and comprises a rate-controlling polymeric matrix comprising of a hydrogel matrix, such as hydroxypropyl methylcellulose, which, when wet, will swell to form a hydrogel thus the rate of release of dalfampridine from this dosage formulation is sustained both by diffusion from the swollen tablet mass and by erosion of the tablet surface over time. The rate of release of dalfampridine may be controlled both by the amount of polymer per tablet and by the inherent viscosities of the polymers used.
However, the administration of the current marketed product, AMPYRA®, should be tightly managed with an approximately 12-hours interval between doses to avoid potential adverse effects, such as seizure. In addition, the drug release profile of a hydrogel matrix system is susceptible to food ingestion and usually results in burst plasma drug concentration, which may cause undesired adverse effects. Besides, the convenience of once daily administration will improve patient compliance and enhances therapeutic effect. Therefore, there is a need to have a dosage form that can provide a steady drug release profile with once daily oral administration of dalfampridine.